How Does Cannabis Kill Cancer Cells?… Part Two

How Does Cannabis Kill Cancer Cells?…Part Two

As described in part one, the cancer cell is a mutated, primitive cell that has lost the cell signalling mechanism for Programmed Cell Death. Perhaps PCD (programmed cell death) has been intentionally silenced by the evil cancer cell. If we could somehow restore and then trigger the pathways for programmed cell death in the cancer cells, we would have ourselves an exceptional cancer treatment. This is the beauty of the phyto-cannabinoids, THC and CBD. which restore programmed cell death signalling in the cancer cells by utilizing whatever pathways are available. If one pathway is blocked, the Cannabinoid signalling finds another pathway to terminate in apoptosis or programmed cell death of the cancer cell..

The “Whack-A Mole” Concept of Programmed Cell Death

This idea of switching among pathways, depending on what is available, is perhaps best described as the “Whack-a-Mole” concept of programmed cell death. Now we can understand why so many differing pathways are utilized by Cannabinoids in the various cancer models studied, all terminating at a common endpoint, programmed cell death (PCD).

Whack -A-Mole is the “the practice of repeatedly getting rid of something, only to have more of that thing appear”. Above Left image courtesy of CitizenThymes.com

Dr Manuel Guzman has devoted his career to the anti-cancer activity of phyto-cannabinoids such as THC (Tetra-Hydo-Cannabinol) and CBD (CannaBiDiol). Left Image courtesy ofManuel Guzman.

Cannabinoids Induce Programmed Cells Death

In an editorial in 2012, Dr Guzman says the anti-cancer effects of Cannabinoids are due to their ability to induce Programmed Cell Death (PCD, apoptosis). In addition, Dr Guzman cites animal experiments showing cannabinoids inhibit new vessel growth in cancerous tissue, block cancer cell invasion of surrounding tissues and block metastasis spread of cancer cells.(1)

Accumulation of Ceramide in Glioma Cells

Dr Guzman has studied Glioma cells extensively,. These are the brain cancer cells, and he reports that THC and other cannabinoids induce programmed cell death (apoptosis) in Glioma cells. The mechanism elucidated so far, is the intra-cellular accumulation of the death signal molecule ceramide,which is triggered by activation of endocannabinoid receptors,CB1 and CB2.(1) Ceramide accumulation in the cell targets the mitochondria, causing autophagosomes to attach to the mitochondria which then undergo mitophagy, (ie they “eat themselves”). Electron microscope studies show loss of mitochondrial inner membranes with ballooning and vacuolization of the mitochondria. As you might expect, this leads to loss of mitochondrial function, and programmed cell death.

CBD- Independent of Cannabinoid Receptors

Cannabidiol, CBD, the non-psychoactive component of cannabis, appears to cause programmed cell death in a manner independent of the CB1 and CB2 receptor system. As reported by McAllister’s group, the anti-cancer effect of CBD seems to be related to downregulation of the ID-1 gene through the ERK/MAPK pathway.(1)

The Mitochondrial “Governator”

A different CBD mechanism of Programmed Cell Death is described in a study by Rimmerman at Tel Aviv University. This involves the VDAC, the Voltage Dependent Anion Channel in the mitochondrial membrane. The VDAC is a key regulator of mitochondrial function and has been dubbed “The Governator”of mitochondrial activity.

Dr. Rimmerman at Tel Aviv University reported in 2013 that CBD acts directly on the VDAC, to open the channels and increase membrane permeability.(6) This allows the release of Cytochrome C into the cytosol which then actives the Caspase proteolytic enzyme cascade, irreversibly triggering the intrinsic pathway for programmed cell death in cancer cells. The exact receptors have yet to be elucidated. (6) Upper left image: Governator courtesy of Huffington Post.

NUPR, the Swiss Knife of Cancer – Stress Related Protein P8

Another possible mechanism for PCD is the P8 pathway. The cannabinoid molecule, THC, upregulates expression of the stress-regulated protein p8 (also known as NUPR1), a transcriptional regulator which causes endoplasmic reticulum (ER) stress, and may trigger programmed cell death via the intrinsic mitochondrial pathway or by autophagy (the cell eats itself).(8) The NUPR1 gene has been dubbed the Swiss Knife of Cancer. This P8/NUPR1 pathway has been shown in glioma cells, pancreatic and hepatic cancer cells. (1,8) Dr Guzman speculates that perhaps this pathway may serve as the main mechanism by which endocannabinoid receptor activation induces PCD, programmed cell death.(1) Left image swiss knife courtesy ofwikimedia commons.

Selective for Cancer Cells – Leaving Normal Cells Unharmed

As mentioned above, THC and CBD are the two major anti-cancer cannabinoids used by the medical marijuana community. These cannabinoids selectively target cancer cells for Programmed Cell Death, while sparing normal cells, which are left unaffected. While considerable progress has been made on the molecular mechanism of programmed cell death in cancer cells, the precise mechanism for the sparing of normal cells, ie.”cancer cell selectivity” has yet to be elucidated.(1)

This type of selectivity is a rare and sought after feature, and as you might imagine, very beneficial for the cancer patient. On the other hand, cytotoxic chemotherapy, the standard of care for cancer patients by the mainstream oncologist, has no selectivity and kills normal cells along with the cancer cells. This lack of selectivity causes well known adverse side effects of chemotherapy including nausea, vomiting, hair loss, chronic fatigue, anemia, neuropathy, etc.

Pilot Study in 9 Glioblastoma Patients

In 2006, Manuel Guzman’s group published their pilot study using THC infused directly into the brain tumor of 9 patients with recurrent malignant glioblastoma. (3) The results of this pilot study were unimpressive. At least the THC did no harm and was well tolerated.(3) There may have been some benefit in two of the patients, and brain biopsy material could be studied revealing the same molecular mechanisms in play as found in the cancer cell culture and animal studies, namely, cancer cells were induced to undergo Programmed Cell Death with evidence of both autophagy and apoptosis.(3) Left Image : typical enhancing Glioblastoma on MRI Brain srudy, courtesy wikimedia commons.

Overly Heroic ?

In my opinion, direct infusion of THC into the brain is overly heroic and completely unnecessary, asexcellent results for malignant brain tumors are currently obtained with oral administration of cannabis oil. The use of cannabis oil was pioneered by Rick Simpson, a Canadian who uploaded a You-Tube video called Run From the Cure which popularized a “Do-It-Your-Self-at-Home” method of making Cannabis Oil for personal medical use.

Mara Gordon of Aunt Zeldas

A more sophisticated approach utilizes Steep Hill Halentlab testing of various cannabis strains to find a combination of two strains providing both THC and CBD in high yield. Mara Gordon of Aunt Zelda’s in California reports good results by combining two cannabis strains, one high in THC and the other high in CBD. Her report describes excellent results with this regimen for pediatric cancer patients, some of which were malignant brain tumors.

The Vacuum Phenomenon- A Dearth of Clinical Studies

As this Pilot Study by Guzman is the only human study of cannabis in Glioblastoma, the complete absence of additional clinical studies is astounding. However, when one realizes cannabis is a natural plant substance which, by definition, cannot be patented and therefore of no interest to the pharmaceutical industry, this becomes more understandable. In addition, like any other natural substance, large scale clinical trials using Cannabis Oil as a cancer treatment are unlikely to ever take place. Instead I expect future randomized clinical trials by drug companies seeking FDA approval on patented molecules or materials derived from the cannabis plant. Examples are drugs such as dronabinol, nabiximols and nabilone.

A Government Paradox

In spite of the obvious rule that natural substances cannot be patented, the US government has apatent on medicinal use of “Cannabinoids as antioxidants and neuroprotectants” (US 6630507 B1). It would appear paradoxical that a US government agency Dept of Health and Human Services(HHS), would hold such as patent, and at the same time another US government agency, the DEA, declare a ruling that Cannabis “has no accepted medical use”. Perhaps the DEA should talk to HHS. People heavily involved in working to promote medicinal cannabis legislation might be enraged by this. However, most other people would simply throw up their hands, shrug their shoulders and say,”Well, that’s the government for you“. Upper left image courtesy of Ronald Reagan Quotes

In Dec 2013, GW Pharmaceuticals announced its patent for use of the Cannabinoids, THC and CBD in a 1:1 ratio, for treating Gliomas. Sativex(R) is their plant-derived cannabinoid prescription drug which has a 1:1 ratio of THC to CBD. A clinical trial of Sativex in recurrent glioblastoma patients is currently underway, and not yet completed.

Paola Massi, PhD is a prolific cannabis researcher at University of Milan in the Department of Cellular and Molecular Pharmacology. Left Image: University of Milan Courtesy of Wikimedia commons.

I recommend to you her 2013 report in the British Journal of Medical Pharmacology entitled, “Medical cannabidiol – is there anything it can’t do?” (8) In this report, Dr Massi says:

” cannabinoids possess anti-proliferative and pro-apoptotic effects and they are known to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization.”(8)

The basic science of cannabis cancer research involves studying cancer cells in cultures by treating them with cannabinoids (mainly THC and CBD) and other agents, after which the cancer cells are studied to determine the effect. A second method is the in-vivo animal study usually done with mice injected with cancer cells (called a xenograft), and then treated with cannabis agents. The mice are observed, later sacrificed and organs studied to determine effect.(8)

Breast Cancer

Vincent DiMarzo’s Group in Italy studied breast cancer in a xenograft animal model. They used subcutaneous injection human breast cancer cells (MDA-MB-231 cells) into mice. Their 2006 paper showed Cannabidiol (CBD) to be the most potent inhibitor of cancer cell growth, with cancer cells undergoing apoptosis. Lung metastases were reduced and inhibited in the mice, as well.(16) Left image courtesy of Vincent DiMarzo.

McAllister’s Group continued this line of study, publishing in 2011 Breast Cancer Research their paper further delineating the pathways by which Cannabidiol reduces breast cancer cell growth, invasion and spread (metastases). They found that CBD works through the ERK/MAPK pathway, and the ROS(Reactive Oxygen Species) pathways, both leading to down-regulation of Id-1 gene, a key gene in cancer biology.

Shrivastava et al. studied the effect of CBD on human breast cell lines and their 2011 paper reported induction of cancer cell death by apoptosis and autophagy. Further studies of the molecular pathways involved, showed ER (endoplasmic reticulum stress) and production of ROS (reactive oxygen species). They found that CBD reduced mitochondrial membrane potential (opened VDAC channels) which released Cytochrome C into the cytosol, and activated programmed cell death through the intrinsic pathway. Going further, with even more elegant studies, Shrivastavs’s group blocked the apoptotic cell death pathway by adding Caspase inhibitors to the CBD treated cancer cells, after which she found compensatory increase in the autophagy pathway of cell death. This supports the “Whack-a-Mole” concept in which blocking one pathway to cell death merely leads to preferential use of an alternate pathway.

Gliomas

Gliomas are cancers which originates in brain tissue, also called glioblastoma, astrocytoma, etc. Gliomas are perhaps the most devastating, tending to be very aggressive with high recurrence rate after chemotherapy and radiation therapy,

Prognosis for this type of cancer is unusually poor even among privileged sectors of our society who can afford “the best” health care. Senator Senator Edward Kennedy, who had access to the most prestigious medical facilities, succumbed to Glioblastoma 15 months after diagnosis, a mere three months longer than the 12.1 month median survival time for the disease. In 2005, a new drug, temozolomide increased median survival time from 12.2 months to 14.6 months, admittedly a small improvement, but not much to brag about. Left Image: Sen Ed Kennedy courtesy of NY Daily News.

Early work from Sweden by Jacobssen published in 2000 showed both THC and CBD inhibited glioma cells in culture with “modest reduction in cell viability”.

A 2004 report by Paola Massi studied the effect of CBD on U87 and U373 human glioma cell lines which appeared to be CB2 receptor dependent and secondary to ROS (reactive oxygen species) generation. When the CBD was added to the brain cancer cells, there was a dramatic reduction in mitochondrial oxidative metabolism, resulting in an anti-proliferative effect and induction of apoptosis, which was partially blocked by addition of a CB2 receptor antagonist, and by anti-oxidant Vitamin E (alpha- tocopherol). In a subsequent xenograft animal model, CBD injected into mice significantly inhibited the growth of implanted human brain cancer cells.

Further studies were done by Massi pubished in a 2006 report, further elucidating the molecular pathways leading to apoptosis by CBD in her human glioma cell model. She demonstrated that Mitochondrial release of cytochrome C, Caspase activation and reactive oxygen species (ROS) induction triggered the apoptosis in the CBD treated human glioma cells. CBD treated normal glioma cells were left unharmed, again showing selectivity.

Further studies published in a 2013 report by Dr. Massi again using CBD treated human glioma cancer cells (U87-MG and T98G cells) showed decreased cell proliferation and invasiveness in the CBD treated cancer cells. Examining protein expression, Dr Massi found the cancer cells pretreated with CBD showed reduction in production of proteins involved in growth, invasion and angiogenesis of the cancer cells. Signalling pathways were studied showing CBD induced down-regulation of ERK, and Akt signaling pathways in glioma cells. There was also decreased hypoxia inducible factor HIF-1α in CBD treated cancer cells. Dr. Massi showed CBD anti-cancer activity utilized multiple pathways, again supporting the “Whack-A-Mole” concept. When one pathway is blocked or absent, another one is used to accomplished PCD, programmed cell death.

Other natural plant substances that inhibit glioma cells: Marchantin C, isolated from the Liverwort plant, was found to produce apoptosis in glioma cells in this 2009 report.

Berberine

Others: Berberine and Plumbagin are additional natural plant substances that induce apoptosis in cancer cells. More studies on Berberine inducing apoptosis in cancer cells can be found here. Similar to the Cannibinoids, Berberine induces apoptosis in cancer cells through the Mitochondrial/Caspase dependent pathway.

Artemesinin ( Chinese Wormwood)

An anti-malarial Chinese herb, artemesia, has been found to have profound anti-cancer activity against multiple cancer cell lines. Studies show induction of apoptosis through mitochondrial pathways. Approximately 400 studies have been published in the scientific literature in recent years. Click on this link: Artemisinin_anti-Cancer_Publications, for the list of publications. Click on this link for an excellent review:Artemisinins_Krishna_Trends_Pharmacological_Science_2008

Reveratrol, Pterostilebene and methyl jasmonate

Reservatrol and its derivative Pterostilbene,from grapes and berries, show strong anticancer activity via induction of apoptosis in cancer cell lines. See my previous article on Pterostilbene. Methyl jasmonate is another plant compound ubiquitous in the plant kingdom which acts directly on the mitochondria to induce apoptosisin cancer cell lines. Methyl Jasmonate was found to work synergistically with other anti-cancer agents such as common chemotherapeutic drugs and glycolysis inhibitors.

Leukemia

Early studies in 2003 by Gallily at Hebrew University in Jerusalem showed cannabidiol (CBD) induced apoptosis via caspase activation in human leukemia cell culture (HL-60 cells). Giving the leukemia cells a short burst of radiation therapy prior to CBD enhanced the effect, attaining a 90-85% cell death rate. Normal white cells were left unharmed.

Continuing Paola Massi’s earlier work, Dr.McKallip’s group published in 2006 their studies of the effect of CBD (cannabidiol) on leukemia cells , again finding CBD induces apoptosis with increased ROS (reactive oxygen species), acting through the CB2 receptor. This is indeed fortuitous, because leukemia and lymphoma cell lines are known to over-express CB2 receptors. (ie Leukemic cells have a higher number of CB2 receptors, and thus are more sensitive to the CB2 mediated effects of CBD.)

Another Patent

Dr. Robert McKallip et al.published a patent in 2004 on the medicinal use of CBD in lymphoma and leukemia.

Lung Cancer

Ramer’s group at the Unviersity of Rostock in Germany has done excellent work on CBD use in lung cancer with a 2012 report published in FASEB. They found early-onset upregulation (four-fold) of ICAM-1 (intercellular adhesion molecule-1) via cannabinoid receptors in CDB treated lung cancer cells. Later, 48 hrs on, they found upregulation of the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) accounting for the loss of invasiveness of the lung cancer cells. In-vivo experiments injecting lung cancer cells (A549, H358, and H460) into mice then treated with CBD showed 2-3 fold increase in ICAM-1 and TIMP-1 protein which decreased cancer cell invasiveness. Upon microscopic inspection, the number of lung metastatic lesions had been reduced in half in the CBD treated mice. In yet another study, Ramers group also discovered a new mechanism, the downregulation of the plasminogen activator inhibitor PAI-1, a protein involved in tumor invasiveness.

CBD Concentrations Similar to Human Use of Sativex

The CBD concentrations used in the Dr Ramer’s animal studies which decreased invasiveness of lung cancer in-vivo were similar to the reported plasma concentrations of CBD ( 2.0-5.0 ng/ml) in healthy volunteers following administration of SativexTM. , the oral mucosal spray product by GW pharmaceuticals which has a 1:1 ratoi of CBD to THC..(reference see theSativex_Product_Monograph_GW_Pharma_CBD_THC)

“Collectively, the non-psychoactive plant-derived cannabinoid CBD exhibits pro-apoptotic and anti-proliferative actions in different types of tumours and may also exert anti-migratory, anti-invasive, anti-metastatic and perhaps anti-angiogenic properties. On the basis of these results, evidence is emerging to suggest that CBD is a potent inhibitor of both cancer growth and spread…..the anticancer effect of this compound seems to be selective for cancer cells, at least in vitro, since it does not affect normal cell lines. The efficacy of CBD is linked to its ability to target multiple cellular pathways that control tumourigenesis through the modulation of different intracellular signalling depending on the cancer type considered.” Massi BJCP 2013.

What is Evidence ?

A word of caution is in order here as to what exacty constitutes evidence. . Although, as you can see, we we have presented many basic science studies on the anti-cancer activity of cannabinoids THC and CBD, mainstream medical doctors will say with a wave of the hand, “none of this is evidence”. There are many anectodal case histories of remission from cancer with the use of medicinal cannabis. Again, mainstream medical doctors will reject this with a wave of the hand, saying, “none of this is evidence”.

For mainstream medicine which is dominated by the drug industry, the only real evidence is the double blind placebo controlled drug trial, typically required for FDA drug approval. As we mentioned above, we don’t have any of these and I don’t expect we ever will for the cannabis plant, or for any plant or natural substance for that matter. The reason for this is that the cannabis plant is a natural substance which cannot be patented, and therefore of little interest to the drug companies who would never imaging spending the millions of dollars on expensive drug studies.

The RCT

We must remember that the randomized controlled trial (RCT) is a type of drug study required for FDA approval of a drug. It is not intended nor is it usually used to initiate a treatment modality. Treatment is usually based on the good doctor’s clinical judgement, which may be based on observational studies, case reports, personal experience, and all other forms of medical evidence described above.

A Vending Machine For the Pharmaceutical Industry

So we are still faced with this criticism from mainstream medicine that our natural substance, the cannabis plant, has no randomized controlled trials. My answer to this is the following: It is an error to believe that the only form of “medical evidence” consists of a double blind placebo controlled drug trial, and all else is “not evidence” Sadly, the art of clinical observation in the practice of medicine has been lost, and Institutional Medicine has transformed into a “vending machine” for the pharmaceutical industry. In order to be a good vending machine, we must give ourselves temporary amnesia, and when convenient, forget about all other forms of medical evidence.

Medical Evidence- Challenge-Rechallenge Proof of Causality

Regarding the anecdotal case reports of medical cannabis non-nonchalantly dismissed by our mainstream medicine colleagues, these anecdotal case reports which include Challenge-Rechallenge-Dechallenge (CRD) are held as the highest level of evidence, and considered proof of causality by our Court System, the FDA and the World Health Organization.

How to Ban a Drug

Let’s say hypothetically a questionable drug is suspected of producing horrendous adverse side effects which, if true, would serve as grounds to ban the drug. The CRD argument is accepted by the court system and the FDA, and is commonly relied upon to prove yes these adverse side effects are indeed caused by the drug in question, and the drug is then banned from the marketplace.

The Randomized Controlled Trial was designed to protect the public from “bad drugs”. However, of all the drugs granted FDA approval based on RCT studies, demonstrating the drug to be more effective compared to placebo, Ten Per Cent are later banned, and another Ten Per Cent are given a “Black Box” Warning. Obviously, there are problems with these Randomized Controlled Trials. The drug companies have corrupted the drug trial system to rig the results in their favor. How do they do it? They use various well known gimmicks such as data manipulation, restricting the entry criteria, Medical Ghost-Writing, with-holding negative results from publication, etc.

An example: The SSRI antidepressant drugs were granted FDA approval based on manipulated studies. Years later, the truth was revealed in a JAMA report. The SSRI drug magnitude of benefit compared to placebo is “minimal or nonexistent” for mild to moderate depression.

Another example: A Double Blind Placebo controlled study was conducted and FDA approval granted in June 2013 for the drug paroxetine, an SSRi antidepressant, as treatment for menopausal symptoms of “hot flashes”. Efficacy over placebo was marginal. In my opinion, the use of psycho-active drugs such as SSRI anti-depressants for treatment of symptoms caused by menopausal hormone deficiency is an abuse and mistreatment of women belonging in a medical museum as an example of medical iatrogenesis. Not only is paroxetine, medically ineffective for treatment of menopausal symptoms (a hormone deficiency state), paroxetine is one of the most addictive of the SSRI drugs, and the FDA has warned that withdrawal from paroxetine can be severe. (BMJ). The drug has numerous adverse side effects including increased suicidal activity , loss of libido and sexual dysfunction. The medical practice of prescribing SSRI antidepressant and other psychiatric drugs for treatment of menopausal symptoms in women borders on criminal behavior by the medical system. This is a medical practice that should be halted immediately.

Here is another example of “temporary amnesia” by our medical colleagues who insist on “evidence” of the randomized drug trial. The popular thyroid medicine, levothyroxine, Synthroid(r), was “Grandfathered In ” and prescribed by practitioners for 46 yearswithout any randomized trials or formal FDA approval. This was rectified in July, 2002 when Synthroid(r) finally received FDA approval. How could doctors prescribe a drug for 46 years without “evidence” ? Solution: Just give yourself temporary amnesia.

Prescribing Natural Substances At the Hospital

The Mainstream Medical Doctor who dismisses natural substances claiming there is “no evidence” must self administer a convenient lapse in memory when they prescribe one of many natural substances listed in the Hospital Formulary. Like the above synthroid (r) example, these have been “GrandFathered In”.

Examples: Parenteral Vitamin C, IV Isotonic Saline, Red Blood cell transfusions, Parenteral thiamine, parenteral B12, IV Magnesium, IV oxytocxin (Pit-Drip) used in obstetrics. There are many more. These are all natural substances which cannot be patented, and therefore no randomized trial will ever be forthcoming.

The Off Label Use of FDA approved Drugs

Again, temporary amnesia is required by our mainstream medicine colleagues for the common practice of prescribing drugs Off-Label. This is the use of a drug for medical indications other than the orginal FDA approved indication. These are drugs anecdotally effective, however, they are off-patent with no randomized controlled trials completed or even to be expected for the off-label use.

An example of this is Clomiphene, FDA approved to induce ovulation in women to increase fertility. Off-label use of clomiphene in young males to increase testosterone levels while preserving fertility is quite effective in observational studies, and verified in my office with challenge-dechallenge-rechallenge type protocols.

Surgical Procedures

When dismissing natural substances, the mainstream practitioner will conveniently suffer from temporary amnesia regarding another point: Many surgical procedures have never been submitted to the rigors of a randomized trial, and when they are, they are sometimes found to be sham procedures. Arthroscopic knee surgery for osteoarthritis and bone marrow transplant for breast cancer were performed for years until the truth was finally revealed. They were no better than placebo.

Why Most Published Research Finding Are False

According to Dr. John P.A. Ioannidis, who published his 2005 article entitled, “ Why Most Published Research Findings Are False“, as much as 90% of the published information in medical journals doctors rely on is flawed. In order to carry on, and survive their day at the clinic or hospital, mainstream medical doctors must again self administer temporary amnesia. They must ignore or forget this unpleasant nonsense about how the published medical information they rely on is biased, unreliable, flawed and downright wrong.

Observational Studies Are Evidence

More examples in which treatment is based on clinical observation studies, and not on randomized controlled trials:

Wernicke’s encephalopathy in infants was reported in Israel caused by thiamine deficient feeding formula. The authors state: “Clinician awareness of the possibility of thiamine deficiency … is important for …prevention of irreversible brain damage. Therapy with large doses of thiamine should be initiated at the earliest suspicion of vitamin depletion, even before laboratory evidence is available.” Thiamin is a natural substance in the body, a vitamin, so there are no randomized controlled trials. This medical practice is based on observational studies.

Folate supplementation is given to child bearing women to prevent neural tube defects. Folate is a natural substance in the body, a vitamin, so there are no RCTs. This medical practice is based on observational studies.

Sudden onset of psychosis and other neurological disease is a treatable cause of B12 deficiency. B12 is a natural substance in the body, a vitamin, so there are no RCTS for B12, and this medical practice is based on observational studies.

Intravenous Vitamin C and other anti-oxidants are given to critically ill patients in the Intensive Care Unit. Vitamin C is a natural substance, a vitamin, so there are no drug company randomized trials. (Vitamin C Saves Life of Dying Man)

Likewise for phyto-cannabinoids which mimic endogenous cannabinoids in the body, similar to the above examples, these are natural substances which cannot be patented and unlikely to ever undergo randomized drug trials.

If you look at the enormous body of scientific knowledge we have with basic science, laboratory and animal studies, observational studies, anecdotal case histories, personal accounts published on the internet, etc, I say this is all “evidence” which massively overshadows and dwarfs the relatively miniscule world of the patented drug study. The volume of publications for patented drugs is only a small fraction of the entire body of medical science knowledge we have accumulated. To reject this larger body of scientific knowledge as “not evidence” is merely a ruse, a form of self-censorship motivated by politics. It’s high time we exposed this as a ruse, no pun intended.